Vaccines are of major importance in controlling the spread of infectious diseases, but use of some vaccines was linked to allergic and autoimmune phenomena in healthy and often in certain high risk populations. Immediate systemic allergic reactions after vaccination with commonly used vaccines are extremely rare to a degree were it can be argued that there is any association at all between the vaccines and the allergic reactions that were reported (1,2).

It has been feared that vaccinations in infancy and childhood can increase the risk of development of asthma and allergic diseases. The concern has been particularly raised in regard to some of the currently available non-replicating infant vaccines that may not mimic a natural infection-mediated immune response that may protect against the development of allergic diseases and asthma. However, there has been no epidemiologic evidence that infant vaccinations with diphtheria, pertussis, tetanus (DPT), measles, mumps, rubella (MMR) and bacillus Calmate-Guerin (BCG) vaccines in infancy are associated with the development of allergic diseases (3,4).

Influenza vaccine

Influenza causes substantial morbidity in adults and children, and vaccination can prevent influenza and its complications. However, there is concern that vaccination may cause exacerbation of asthma. Despite recommendations in most countries for giving inactivated influenza vaccine to people with asthma, only a minority currently receive it. One reason for low vaccine coverage has been concern that vaccination may induce exacerbations of asthma. Most studies to date present strong evidence that influenza vaccinations are not associated with increased risk for atopy and do not alter bronchial reactivity or lung function, asthma symptoms, exacerbations, or increased use of rescue medications (5-17). The inactivated and the more recently introduced live attenuated influenza vaccines are, therefore, safe to administer to adults and children. Annual influenza vaccination is recommended by the Advisory Committee for Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the Expert Panel for the Diagnosis and Management of Asthma to protect asthmatic patients (18). It is recommended that in view of the morbidity of influenza, all those with asthma should receive the vaccine annually. Current recommendations of the American Academy of Pediatrics are that children with asthma receive the inactivated vaccine and should not receive the live attenuated vaccine.

Bacillus Calmette-Guerin (BCG)

The association between mycobacterial exposure, vaccination with bacillus Calmette-Guerin (BCG) in early life and atopy remains controversial.

There are conflicting reports on the effect of BCG vaccination on the subsequent development of atopy and asthma in children. One of the problems in attempting to interpret the results is that all the studies have not tested the relationship in the same way. Some studies examined tuberculin response. Others investigated BCG vaccination; some investigated both; and tuberculosis infection has also been investigated. Outcomes measured also differed and included asthma, defined in a number of different ways; atopy; and manifestations of atopic disease, as well as respiratory symptoms, such as wheeze. When a review of the literature is restricted to BCG vaccination and wheeze, conflicting results are still seen (19-27).

BCG vaccination is thought to be among a group of vaccines capable of manipulating the immune system toward T(H)1 dominance and therefore reducing the likelihood of atopic disease. In the murine system, BCG inhibits allergic sensitization and airway hyper-reactivity. Some epidemiological studies in humans suggest an inhibitory effect of tuberculosis on allergy. BCG vaccination in children, however, has no or merely a marginal suppressive effect on atopy. BCG vaccination in adult patients with moderate-to-severe asthma improved lung function and reduced medication use. This amelioration was accompanied by a suppressed Th2-type immune response, suggesting that BCG vaccination might be an effective therapeutic modality against asthma. It is unknown if neonatal BCG vaccination affect cytokine responses of lymphocytes that are exposed in vitro to allergens. A few studies examined if neonatal BCG vaccination or, alternatively, immunologic memory of this vaccination is associated with a reduced prevalence of allergic sensitization, asthma, eczema, and hay fever during childhood. So far there are conflicting results if BCG vaccination may protect against development of allergic diseases, particularly when given just after birth. Currently, there is no evidence for asthma exacerbations related to BCG vaccination.

Pertussis

Pertussis infection has been suspected to be a potential causal factor in the development of atopic disease because of the effect of pertussis immunization on specific IgE antibodies. Pertussis vaccination in infancy has been suggested to increase the risk for development of asthma and allergy. The acellular pertussis vaccine has replaced the whole-cell inactivated vaccine in many countries, but it is still widely used outside Europe and North America. There have been conflicting results as to the risk of atopy related to pertussis (27-34). A meta-analysis of 7 studies, of pertussis with a total of 186,663 patients showed no or only borderline significant provocative effect on asthma between whole-cell pertussis vaccination and incidence rates of asthma during childhood and adolescence (27). None of the studies reported an acute exacerbation following pertussis vaccination.

Pneumococcal vaccine

Allergic and especially anaphylactic reactions to pneumococcal vaccine are very rare. Because of the presence of specific IgE antibodies and positive skin test in such cases it is assumed that these reactions are IgE mediated. The safety of pneumococcal vaciines was recently analyzed in a systematic review of 42 studies (35). PCV7 vaccination which was introduced and licensed in the United States in 2000 may result in more local reactions and fever than certain comparison vaccines. Two of the largest studies of PCVs, one involving PCV7 and the other, PCV9, found a statistically significant increased risk of hospitalization for reactive airway disease, including asthma. The largest trial (36) included 19,922 infants vaccinated with PCV9 at 6, 10 and 14 weeks and 19,914 infants who received placebo injections. Hospitalization for asthma or reactive airway disease beyond 31 days after vaccination was more frequent in the PCV9 than in the placebo group, with a relative risk of 1.79 (P = 0.009). The biologic plausibility of such events beyond one month after vaccination in regard to possible effect of vaccination is indeed questionable. Another large trial of PCV9, however, did not find an increased risk of asthma. There were no major safety problems with PCV7 or any other pneumococcal conjugate vaccine, with the possible exception of reactive airway disease, which therefore requires further follow-up.

Other infant vaccinations

Three other important vaccines are part of the vaccination protocols for infants and children namely Measles mumps and rubella (MMR), Polio and Haemophilus influenzae type b vaccination (Hib) (37,38). None of these vaccines increase the risk of atopy or asthma, and none of them was reported to exacerbate asthma.

Reactions to vaccine components

Allergic reactions to different vaccines may result from reactions to the common components of these vaccines. Two main components that were identified are gelatin and egg protein.

The risk of gelatin was primarily assessed in vaccination with DTP (39,40). There was a strong causal relationship between gelatin-containing DTaP vaccination, anti-gelatin IgE production, and risk of anaphylaxis from immunization with live viral vaccines which contain a larger amount of gelatin. The mechanism of the reaction remains unknown.

Egg allergy is a special challenge in influenza vaccination programs. Influenza vaccines are derived from the extra embryonic fluid of chicken embryos inoculated with specific types of influenza virus. The vaccines typically contain small but measurable quantities of egg protein allergens, such as ovalbumin. Adverse allergic reactions have been seen in patients with egg allergy injected with inactivated influenza vaccines. The prevalence of egg allergy in the population is estimated between 0.13%, and reaches 1.6% in young children. The prevalence is higher in allergic children in general, 5.6%, and up to 40% in children with moderate to severe atopic dermatitis. The prevalence of egg allergy in asthmatic children is between 2.0 to 3.6%. Even in egg allergy the risk of influenza vaccination is extremely low (41,42). It is recommended that in all patients one should inquire about a history of adverse reactions to egg or influenza vaccines before vaccination. Current recommendations by the American Academy of Pediatrics are that children with any known systemic reactions to egg should not receive influenza vaccines whether inactivated or live attenuated vaccines, but that less severe or local reactions are not contraindications. Recommendations by the Advisory Committee on Immunization Practices are that persons who have had hives or swelling of the lips or tongue, or who have experienced acute respiratory distress or who collapse after eating eggs, should consult a physician for appropriate evaluation to help determine if vaccine should be administered (18). Persons who have documented immunoglobulin E (IgE)-mediated hypersensitivity to eggs, including those who have had occupational asthma related to egg exposure or other allergic responses to egg protein, also might be at increased risk for allergic reactions to influenza vaccine, and consultation with a physician before vaccination should be considered. In the same document the Advisory Committee for Immunization Practices recommends that TIV or LAIV should not be administered to persons known to have anaphylactic hypersensitivity to eggs or to other components of the influenza vaccine. Prophylactic use of antiviral agents is an option for preventing influenza among such persons. In view of the importance of influenza vaccination, the rarity of life threatening reactions, and the safety of MMR vaccination in egg allergic children, these recommendations could be challenged so that Influenza vaccine is contraindicated only in patients with severe anaphylactic reaction after egg ingestion. The Centers for Disease Control (CDC), based on ACIP statement on MMR, now recommend routine vaccination of egg-allergic children without the use of special protocols or desensitization procedures.

Commentary

Vaccination was linked to potential allergic side effects including exacerbations of asthma in healthy and often in certain high risk populations. Careful examination of the literature shows such reactions are rare and life threatening event are extremely uncommon. One should distinguish between two groups of vaccinations: Those against general infectious diseases like DTP, MMR, Polio, Hib, and those against mainly respiratory viral diseases represented best by the vaccination towards influenza. The latter are of major importance in regard to asthma exacerbations in terms of either possible prevention or exacerbation following vaccination. Current studies show that childhood vaccines including inactivated and live attenuated influenza vaccines are safe for children with mild intermittent asthma 18 months of age and older. There is concern regarding possible increased wheezing and hospital admissions in infants given live attenuated influenza vaccination through the intranasal route, and further studies are needed. Meanwhile, children with frequent wheezing or more severe asthma should receive the inactivated influenza vaccine. Although severe allergic adverse events attributable to vaccination are extremely rare, all serious allergic reactions should be further assessed to detect the likely causative vaccine component, including egg protein and gelatin.

The risks of not vaccinating children far outweigh the risk for allergy and asthma exacerbations. Therefore, childhood vaccination should remain an essential part of child health programs and should not be withheld, even from children with asthma or predisposed for allergy.

View to the future

Vaccination in children with asthma can be expected to improve in three major areas: Diagnosis, safety and efficacy.

A fundamental problem in attempts to investigate the occurrence and possible exacerbation of asthma following vaccination is the lack of a standardized, universally accepted definition of asthma especially in infants. Wheeze has been identified as the most important symptom because it can be measured relatively easily, without invasive or expensive tests. It is frequently used as an outcome measure in questionnaire-based epidemiologic studies. The development of better diagnostic markers of inflammation for asthma such as NO measurements may help in the more accurate diagnosis. Similarly, better and faster means to diagnose viral infections using molecular biologic techniques such as PCR, will help to elucidate whether wheezing following vaccinations is causally related to the vaccination or a result of an intercurrent illness related to other and non-related viral infections.

The experiments with intranasal administration of inactivated whole influenza vaccine to mice which reduced subsequent allergen sensitization and prevented allergen-induced AHR, suggest that the composition of the influenza vaccine has a major influence on subsequent development of allergen-induced sensitization and AHR, and suggest that mucosal vaccination may represent a step towards the development of a preventive strategy for atopic asthma. A potential development can be sublingual vaccination similar to that of sublingual immunotherapy, which is in general safer than sublingual immunotherapy. The nasal and potentially sublingual route of administration may be better accepted by children, easier to administration, and may lead to increase in the vaccination rates in the population. Further studies are needed to examine the safety of live attenuated influenza vaccine in children with wheezing and asthma.

Finally, improvement in the diagnosis of asthma exacerbations related to vaccinations and safer and more efficacious vaccines, will lead to better assessment of the cost effectiveness of various vaccines, especially that of influenza. In this regard, some studies revealed that influenza vaccination did not result in a significant reduction of the number, severity, or duration of asthma exacerbations caused by influenza. Additional studies will be needed to justify routine influenza vaccination of children with asthma.

Key Issues

The prevalence of asthma and allergic diseases has increased in recent decades. Asthma exacerbations often result from respiratory viral infections.

Vaccines have had a major effect on controlling the spread of infectious diseases, but there has been concern that vaccinations in infancy and childhood can increase the risk of development of asthma and allergic diseases in healthy and often in certain high risk populations.

Vaccination programs do not explain the increasing prevalence of allergic diseases and asthma. Immediate systemic allergic reactions including asthma exacerbations after vaccination with commonly used vaccines are very rare. Severe allergic adverse events attributable to vaccination including asthma exacerbations are extremely rare and life threatening event are extremely uncommon.

Serious allergic reactions should be further assessed to detect the likely causative vaccine component, including egg protein and gelatin.

Influenza vaccines both inactivated and live attenuated are safe in children with mild intermittent asthma, but there is concern regarding possible increased wheezing and hospital admissions in infants given live intranasal vaccination.

Further studies are needed to justify routine influenza vaccination of children with asthma.

The risks of not vaccinating children far outweigh the risk for allergy and asthma. Therefore, childhood vaccination should remain an essential part of child health programs and should not be withheld, even from children with asthma or predisposed for allergy.

Conclusion

Vaccination was linked to potential allergic side effects in healthy and often in certain high risk populations. Careful examination of the literature shows such reactions are rare and life threatening event are extremely uncommon. Although severe allergic adverse events attributable to vaccination are extremely rare, all serious allergic reactions should be further assessed to detect the likely causative vaccine component, including egg protein and gelatin. Vaccination programs do not explain the increasing prevalence of allergic diseases, but individual children may uncommonly develop an allergic reaction to a vaccine. The risks of not vaccinating children, however, far outweigh the risk for allergy. Therefore, childhood vaccination remains an essential part of child health programs and should not be withheld, even from children predisposed for allergy. Immunotherapy provides an efficacious and safe method for treatment of allergic conditions by immunomodulation of the immune system. The possibility of vaccination triggering or unmasking autoimmunity in genetically susceptible individuals cannot be ruled out, but for the general population the risk: benefit ratio is overwhelmingly in favor of vaccinations.

Marks GB, Ng K, Zhou J, Toelle BG, Xuan W, Belousova EG, Britton WJ. The effect of neonatal BCG vaccination on atopy and asthma at age 7 to 14 years: an historical cohort study in a community with a very low prevalence of tuberculosis infection and a high prevalence of atopic disease. J Allergy Clin Immunol. 111(3), 541-549 (2003).